Document Detail


Reduced maximal inhibition in phenotypic susceptibility assays indicates that viral strains resistant to the CCR5 antagonist maraviroc utilize inhibitor-bound receptor for entry.
MedLine Citation:
PMID:  17182681     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Maraviroc is a CCR5 antagonist in clinical development as one of a new class of antiretrovirals targeting human immunodeficiency virus type 1 (HIV-1) coreceptor binding. We investigated the mechanism of HIV resistance to maraviroc by using in vitro sequential passage and site-directed mutagenesis. Serial passage through increasing maraviroc concentrations failed to select maraviroc-resistant variants from some laboratory-adapted and clinical isolates of HIV-1. However, high-level resistance to maraviroc was selected from three of six primary isolates passaged in peripheral blood lymphocytes (PBL). The SF162 strain acquired resistance to maraviroc in both treated and control cultures; all resistant variants were able to use CXCR4 as a coreceptor. In contrast, maraviroc-resistant virus derived from isolates CC1/85 and RU570 remained CCR5 tropic, as evidenced by susceptibility to the CCR5 antagonist SCH-C, resistance to the CXCR4 antagonist AMD3100, and an inability to replicate in CCR5 Delta32/Delta32 PBL. Strain-specific mutations were identified in the V3 loop of maraviroc-resistant CC1/85 and RU570. The envelope-encoding region of maraviroc-resistant CC1/85 was inserted into an NL4-3 background. This recombinant virus was completely resistant to maraviroc but retained susceptibility to aplaviroc. Reverse mutation of gp120 residues 316 and 323 in the V3 loop (numbering from HXB2) to their original sequence restored wild-type susceptibility to maraviroc, while reversion of either mutation resulted in a partially sensitive virus with reduced maximal inhibition (plateau). The plateaus are consistent with the virus having acquired the ability to utilize maraviroc-bound receptor for entry. This hypothesis was further corroborated by the observation that a high concentration of maraviroc blocks the activity of aplaviroc against maraviroc-resistant virus.
Authors:
Mike Westby; Caroline Smith-Burchnell; Julie Mori; Marilyn Lewis; Michael Mosley; Mark Stockdale; Patrick Dorr; Giuseppe Ciaramella; Manos Perros
Publication Detail:
Type:  In Vitro; Journal Article     Date:  2006-12-20
Journal Detail:
Title:  Journal of virology     Volume:  81     ISSN:  0022-538X     ISO Abbreviation:  J. Virol.     Publication Date:  2007 Mar 
Date Detail:
Created Date:  2007-02-12     Completed Date:  2007-03-27     Revised Date:  2013-11-25    
Medline Journal Info:
Nlm Unique ID:  0113724     Medline TA:  J Virol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2359-71     Citation Subset:  IM    
Data Bank Information
Bank Name/Acc. No.:
GENBANK/EF367173;  EF367174;  EF367175;  EF367176;  EF367177;  EF367178;  EF367179;  EF367180;  EF367181;  EF367182;  EF367183;  EF367184;  EF367185;  EF367186;  EF367187;  EF367188;  EF367189;  EF367190;  EF367191;  EF367192;  EF367193;  EF367194;  EF367195;  EF367196;  EF367197;  EF367198;  EF367199;  EF367200;  EF367201;  EF367202;  EF367203;  EF367204;  EF367205;  EF367206;  EF367207;  EF367208;  EF367209;  EF367210;  EF367211;  EF367212;  EF367213;  EF367214;  EF367215;  EF367216;  EF367217;  EF367218;  EF367219;  EF367220;  EF367221;  EF367222;  EF367223;  EF367224;  EF367225;  EF367226;  EF367227;  EF367228;  EF367229;  EF367230;  EF367231;  EF367232;  EF367233;  EF367234
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Amino Acid Substitution
Cell Line
Cyclohexanes / pharmacology*
Drug Resistance, Viral / genetics
Genes, env
Genetic Variation
HIV Envelope Protein gp120 / genetics
HIV Fusion Inhibitors / pharmacology*
HIV Infections / drug therapy,  virology
HIV-1 / drug effects*,  genetics,  pathogenicity,  physiology*
Humans
Lymphocytes / virology
Molecular Sequence Data
Mutagenesis, Site-Directed
Peptide Fragments / genetics
Phenotype
Receptors, CCR5 / antagonists & inhibitors*
Receptors, CXCR4 / antagonists & inhibitors
Triazoles / pharmacology*
Virus Cultivation
Virus Replication / genetics
Chemical
Reg. No./Substance:
0/Cyclohexanes; 0/HIV Envelope Protein gp120; 0/HIV Fusion Inhibitors; 0/HIV envelope protein gp120 (305-321); 0/Peptide Fragments; 0/Receptors, CCR5; 0/Receptors, CXCR4; 0/Triazoles; MD6P741W8A/maraviroc
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